The present invention is directed to the use of certain amidoamines to treat or prevent infections attributable to Acanthamoeba, fungi or combinations of these two types of microorganisms. The invention is particularly directed to the use of the amidoamines described herein to treat or prevent infections of the eye, ear, nose or throat. The pharmaceutical compositions and methods of treatment described herein are also useful in the topical treatment of dermatological infections.
The compositions of the present invention are particularly useful in treating or preventing ophthalmic infections, especially infections of the cornea. Infections of the cornea frequently lead to a serious inflammatory condition known as “keratitis”. If such infections are left untreated, or if the selected therapy proves to be ineffective, Acanthamoeba and fungal infections of the cornea can lead to a rapid destruction of corneal tissues and, ultimately a loss of vision in the affected eye(s).
Various types of agents are currently utilized to treat Acanthamoeba infections. The agents utilized include cationic antiseptics, such as chlorhexidine and polyhexamethylene biguanide (“PHMB”); aromatic diamides, such as propamidine isethionate; and aminoglycoside antibiotics, such as neomycin. Of these agents, the cationic antiseptics chlorhexidine and PHMB are generally considered to be the most effective. However, the efficacy of all of these agents in treating Acanthamoeba infections is fairly limited. Some of the agents have a limited ability to eradicate Acanthamoeba, particularly at the low concentrations required to avoid toxicity to the cornea or other affected tissues, while other agents are inherently toxic to tissues, particularly if prolonged therapy of several weeks or months is required to eradicate the infection.
As with Acanthamoeba infections, fungal infections are relatively rare, but are difficult to treat effectively. The difficulty in treating these infections is due to the limited ability of therapeutic agents to eradicate fungi in situ and the toxic effects of most therapeutic agents on the affected tissues or surrounding tissues.
The following publications may be referred to for further background regarding the current therapies for treating Acanthamoeba and fungal infections of the cornea and associated ophthalmic tissues:    1. Kosrirukvongs, P., et al., “Treatment of Acanthamoeba keratitis with chlorhexidine” Ophthalmology, vol. 106 (4), pages 798-802 (1999);    2. Tien, S. H., et al., “Treatment of Acanthamoeba keratitis combined with fungal infection with polyhexamethylene biguanide. Koahsiung J. Med. Sci., vol. 15, pages 665-673 (1999);    3. Claerhout, I., et al., “Acanthamoeba keratitis: a review” Bull. Soc. Belge. Ophthalmol., vol. 274, pages 71-82 (1999);    4. Lindquist, T. D., “Treatment of Acanthamoeba keratitis” Cornea., vol. 17 (1), pages 11-16 (1998);    5. Gatti, S., et al., “In-vitro effectiveness of povidone-iodine on Acanthamoeba isolates from human cornea” Antimicrob. Agents. Chemother, vol. 42 (9), pages 2232-2234 (1998);    6. Murdoch, D., et al., “Acanthamoeba keratitis in New Zealand, including two cases with in-vivo resistance to polyhexamethylene biguanide” Aust. N. Z. J. Ophthalmol., vol. 26 (3), pages 231-236 (1998);    7. Illingworth, C. D., et al., “Acanthamoeba keratitis” Surv. Ophthalmol, vol. 42 (6), pages 493-508 (1998);    8. Azuara Blanco, A., et al., “Successful medical treatment of Acanthamoeba keratitis” International Ophthalmol., vol. 21 (4), pages 223-227 (1998);    9. Duguide, I. G., et al., “Outcome of acanthamoeba keratitis treated with polyhexamethyl biguanide and propamidine” Ophthalmol., vol. 104 (10), pages 1587-1592 (1997);    10. Hargrave, S. L., et al., “Results of a trial of combined propamidine isethionate and neomycin therapy of acanthamoeba keratitis—Brolene Study Group” Ophthalmol., vol. 106 (5), pages 952-957 (1999);    11. Amoils, S. P., et al., “Acanthamoeba keratitis with live isolates treated with cryosurgery and fluconazole” Am. J. Ophthalmol., vol. 127 (6), pages 718-720 (1999);    12. Navarro-Guerrero, J., et al., “Short communications: a case of bilateral Acanthamoeba keratitis” Farm Hosp., vol. 22 (5), pages 253-255 (1998);    13. Park, D. H., et al., “The role of topical corticosteroids in the management of Acanthamoeba keratitis” Cornea., vol. 16 (3), pages 277-283 (1997);    14. Chung, M. S., et al., “Fungal keratitis after laser in-situ keratomileusis: a case report” Cornea., vol. 19 (2), pages 236-237 (2000);    15. Rodriguez-Ares, T., et al., “Acremonium keratitis in a patient with herpetic neutrotrophic corneal disease” Acta. Ophthalmol. Scandinavica., vol. 78 (1), pages 107-109 (2000);    16. Rahman, M. R., et al., “Trial of chlorhexidine gluconate for fungal corneal ulcers” Ophthalmic Epidemiol., vol. 4 (3), pages 141-149 (1997);
Acanthamoeba is a common soil and water amoeba characterized by a feeding and dividing trophozoite and resistant cyst stage. The organism is an opportunistic pathogen of humans, causing a potentially blinding keratitis most frequently seen in contact lens wearers. The resistance of the cyst stage to most antimicrobial agents makes acanthamoeba keratitis one of the most difficult ocular infections to manage successfully. Although significant advances in the management of acanthamoeba keratitis have been achieved through the use is of polyhexamethylene biguanide and chlorhexidine (0.02% topical application) treatment failures still occur necessitating surgical intervention with penetrating keratoplasty or, ultimately, enucleation.
The above-discussed difficulties in treating ophthalmic infections and associated inflammation attributable to Acanthamoeba and fungi are also seen in the treatment of other tissues infected with these microorganisms. This is particularly true with respect to otic and nasal infections.
In view of the foregoing, there is a need for a more effective means of treating Acanthamoeba and fungal infections. A therapy that provides for more effective eradication of Acanthamoeba and fungi with less potential for toxicity to the infected tissues is particularly needed. The present invention is directed to satisfying these needs.